An HIV transgenic mouse model has been established which exhibits some of the clinical manifestations seen in AIDS. Homozygous animals are born runted and usually die of wasting within 30 days of birth. Heterozygous animals are born with normal weight, but often develop nephropathy as adults. Histologically, the microcystic changes seen in the mouse kidney sections are similar to those seen in samples with HIV patients with renal disease. HIV transgenic mice exhibit additional abnormalities, including myopathy/myositis, lymphadenopathy, and papillomatous lesions of the skin. Given the similarities between the HIV transgenic phenotype and human AIDS, the HIV transgenic mouse system may provide a useful model to study HIV gene therapy. We have focuses our efforts on the development of therapeutic strategies based on the molecular regulation and life cycle of HIV. We have initiated experiments with antisense oligonucleotides, multimers of the TAR sequence, and ribozymes as pilot studies to evaluate gene therapy in this system. Transgenic animals have been developed containing multimers of HIV-1 TAR under the control of the HIV-1 LTR and an HIV specific ribozyme expressed from the human beta-actin promoter. Results of genetic crosses with HIV transgenic animals may demonstrate the efficacy of these novel gene therapy strategies.